Synthesis of biologically active bis-triazolyl dimers of purine and purine isosters

Cilj ovog rada bila je sinteza novih potencijalno biološki aktivnih 1,4-disupstituiranih bis-1,2,3-triazolilnih dimera 6-supstituiranih-7-deazapurina (6a–6d, 8c, 8d, 9a, 9c, 9d) i 6-supstituiranih purinskih analoga (11a–11d, 13a, 13b, 13d, 15a, 15c, 15d). Purinski spojevi su alkiliranjem s 1,2-dibrometanom prevedeni u N-brometilne derivate (2a–2e), iz kojih su potom nukleofilnom supstitucijom priređeni odgovarajući azidi (3a–3e). Bis-triazolni derivati pripravljeni su "klik" reakcijom, azid-alkin cikloadicijom kataliziranom bakrom(I), između odgovarajućeg azida i 4 različita terminalna dialkina. Reakcije dobivanja bis-1,2,3-triazolilnih dimera provedene su u različitim uvjetima: primjenom ultrazvuka, klasičnom sintezom pri sobnoj temperaturi te uporabom dušikovog liganda, N,N-diizopropiletilamina (DIPEA). Rezultati pokazuju da klasični sintetski pristup i uporaba dušikovog liganda pogoduju stvaranju mono-1,2,3-triazolilnog alkina (7b, 7d, 12a–12c, 14b, 14c, 16a, 16c, 16d) te da se primjenom ultrazvuka postiže veća selektivnost i znatno skraćuje reakcijsko vrijeme. Konačno, amino-derivati bis-1,2,3-triazolilnih purinskih dimera (11a–11d, 13a–13d, 15a, 15c, 15d) priređeni su u mikrovalnom reaktoru supstitucijom halogenog atoma na purinskim bazama odgovarajućim aminom uz primjenu vode kao otapala. Strukture svih priređenih spojeva potvrđene su 1H i 13C NMR spektroskopijom te masenom spektrometrijom.The aim of this work was the synthesis of novel potentially biologically active 1,4-disubstituted bis-1,2,3-triazolyl dimers with purine isosteres such as 6-substituted-7-deazapurines (6a–6d, 8a–8d, 9a–9d) and 6-substituted purine analogs (11a–11d, 13a–13d, 15a, 15c, 15d). Purine compounds were alkylated with 1,2-dibromoethane to obtain N-bromoethynyl derivatives (2a–2e), which were subsequently transformed by substitution into corresponding azides (3a–3e). Bis-triazolyl derivatives were prepared by copper-catalyzed "click" chemistry approach using corresponding azides and various terminal dialkynes. Reactions to obtain bis-1,2,3-triazolyl dimers were carried out applying different conditions such as: ultrasonic irradiation, classic synthesis at room temperature and using nitrogen ligand, N,N-diisopropylethylamine (DIPEA). Results show that formation of mono-1,2,3-triazolyl alkyne (7b, 7d, 12a–12c, 14b, 14c, 16a, 16c, 16d) side-product occured in classic synthesis and using nitrogen ligand. On the other hand, the ultrasonic irradiation contributed to higher reaction selectivity and significantly reduced the time of reaction. Finally, amine derivatives of bis-1,2,3-triazoles (11a–11d, 13a–13d, 15a, 15c, 15d) were prepared under microwave irradiation by substitution of the halogen atom on purine ring with corresponding amine in an aqueous medium. The structures of all synthesized compounds were confirmed by 1H i 13C NMR spectroscopy and mass spectrometry